本期文献列表【1-8为综述，9-12为文章】

1.     获得性抵抗免疫检查点抑制剂

Acquired Resistance to Immune Checkpoint Inhibitors

2.     用单细胞基因组学推进癌症研究和医学

Advancing Cancer Research and Medicine with Single-Cell Genomics

3.     肿瘤内异质性：治疗抵抗的罗塞塔石

Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

4.     基于液体活检的治疗反应和耐药生物标志物

Liquid Biopsy-Based Biomarkers of Treatment Response and Resistance

5.     克服乳腺癌内分泌抵抗

Overcoming Endocrine Resistance in Breast Cancer

6.     CDK4/6抑制的敏感性和抗性机制

Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition

7.     对BCR-ABL1靶向治疗的反应和耐药性

Response and Resistance to BCR-ABL1-Targeted Therapies

8.     在KRAS驱动的肿瘤中靶向MAPK通路

Targeting the MAPK Pathway in KRAS-Driven Tumors

9.     弥漫性大B细胞淋巴瘤遗传亚型的概率分类工具及其治疗意义

A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications

10.  1000例儿童低级别胶质瘤的分子与临床综合分析

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas

11.  CHD1的丢失通过染色质失调促进对AR靶向治疗耐药的异质性机制

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation

12.  KMT2D缺乏会损害超级增强子，从而导致肺癌的糖酵解脆弱性

KMT2D Deficiency Impairs Super-Enhancers to Confer a Glycolytic Vulnerability in Lung Cancer

 本期文献摘要

1. 获得性抵抗免疫检查点抑制剂

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30157-4

免疫检查点抑制剂（ICIs）迅速改变了多种肿瘤类型的治疗环境，为一些患者提供了前所未有的生存率。尽管对ICI的反应具有特征性的持久性，但不幸的是，许多最初有反应的患者后来会发展成获得性抵抗。目前对ICIs获得性耐药机制的认识非常有限，可能会抑制下一代免疫疗法的有效发展。在这里，我们研究进展的障碍和新的临床报告询问获得性抵抗，目的是为了在将来克服获得性抵抗的ICIs。

Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.

2. 用单细胞基因组学推进癌症研究和医学

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30148-3

单细胞测序（SCS）已经影响到癌症研究的许多领域，提高了我们对肿瘤内异质性、肿瘤微环境、转移和治疗耐药性的认识。SCS技术的发展和完善导致了成本的大幅度降低、细胞通量的增加和可重复性的提高，为临床应用铺平了道路。然而，在实现转化应用之前，必须克服一些逻辑和技术方面的挑战。这篇综述讨论了过去的癌症研究，新兴技术和未来的临床应用，这些都将改变癌症医学。

Single-cell sequencing (SCS) has impacted many areas of cancer research and improved our understanding of intratumor heterogeneity, the tumor microenvironment, metastasis, and therapeutic resistance. The development and refinement of SCS technologies has led to massive reductions in costs, increased cell throughput, and improved reproducibility, paving the way for clinical applications. However, before translational applications can be realized, there are a number of logistical and technical challenges that must be overcome. This review discusses past cancer research studies, emerging technologies, and future clinical applications that are bound to transform cancer medicine.

3. 肿瘤内异质性：治疗抵抗的罗塞塔石

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30147-1

我们对肿瘤发生的分子机制的理解已经转化为针对特定致癌信号靶点的基于知识的治疗。这些疗法常常在易感肿瘤中引起剧烈反应。不幸的是，大多数晚期癌症，包括那些最初反应强烈的癌症，最终对靶向治疗产生抵抗并复发。尽管基于免疫的疗法更有可能获得完全治愈，但获得性抵抗仍然是其成功的障碍。获得性耐药是肿瘤内存在的异质性和治疗过程中不断变化的直接结果，它使一些肿瘤细胞能够在治疗过程中存活下来，并促进新的抗治疗表型的发展。在这篇综述中，我们讨论了肿瘤内异质性的来源，以及在临床决策过程中捕捉和解释异质性的方法。最后，我们概述了通过直接针对肿瘤内异质性提高治疗效果的潜在策略。

Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity.

4.  基于液体活检的治疗反应和耐药生物标志物

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30152-5

预测性生物标记物有助于选择针对个体肿瘤内分子变化的个性化治疗。患者对靶向治疗的反应通常伴随着治疗抵抗。在这里，我们调查液体活检作为替代肿瘤活检，以评估预测和治疗反应生物标记物。我们检查液体活检的潜力，以满足在治疗意图治疗后，早期发现疾病复发的最小残留疾病监测的挑战。我们关注血液，最常用的微创临床样本，以及两种研究最广泛的检测方法，循环肿瘤DNA和循环肿瘤细胞。

Predictive biomarkers aid selection of personalized therapy targeted to molecular alterations within an individual's tumor. Patients' responses to targeted therapies are commonly followed by treatment resistance. Here, we survey liquid biopsies as alternatives to tumor biopsies to assess predictive and therapy response biomarkers. We examine the potential of liquid biopsies to meet the challenges of minimal residual disease monitoring after curative intent treatment for earlier detection of disease recurrence. We focus on blood, the most commonly collected minimally invasive clinical sample, and on the two most widely studied assays, circulating tumor DNA and circulating tumor cells.

5. 克服乳腺癌内分泌抵抗

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30149-5

雌激素受体阳性（ER+）乳腺癌是最常见的乳腺癌亚型。雌激素受体+乳腺癌的治疗包括抑制雌激素产生和/或直接靶向雌激素受体的干预（整体标记为内分泌治疗）。虽然内分泌治疗大大降低了乳腺癌的复发率和死亡率，但对这种治疗的新发和获得性耐药仍然是一个重大挑战。越来越多的内分泌抵抗机制被报道，包括体细胞改变、表观遗传改变和肿瘤微环境的改变。本文就近年来内分泌治疗耐药机制的研究进展和克服内分泌治疗耐药的可能策略作一综述。

Estrogen receptor-positive (ER+) breast cancer is the most common breast cancer subtype. Treatment of ER+ breast cancer comprises interventions that suppress estrogen production and/or target the ER directly (overall labeled as endocrine therapy). While endocrine therapy has considerably reduced recurrence and mortality from breast cancer, de novo and acquired resistance to this treatment remains a major challenge. An increasing number of mechanisms of endocrine resistance have been reported, including somatic alterations, epigenetic changes, and changes in the tumor microenvironment. Here, we review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance.

6. CDK4/6抑制的敏感性和抗性机制

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30150-1

抑制细胞周期激酶CDK4和CDK6对晚期激素阳性乳腺癌有显著的治疗作用。然而，这种策略的有效性受到先天或后天抵抗机制的限制，其在其他肿瘤类型中的应用尚不确定。在这里，通过对敏感性和耐药机制的综合分析，我们讨论了CDK4/6抑制剂与现有靶向治疗、免疫治疗或经典化疗的联合应用，以期改善CDK4/6抑制剂在各种癌症中的未来治疗应用。

Inhibiting the cell-cycle kinases CDK4 and CDK6 results in significant therapeutic effect in patients with advanced hormone-positive breast cancer. The efficacy of this strategy is, however, limited by innate or acquired resistance mechanisms and its application to other tumor types is still uncertain. Here, through an integrative analysis of sensitivity and resistance mechanisms, we discuss the use of CDK4/6 inhibitors in combination with available targeted therapies, immunotherapy, or classical chemotherapy with the aim of improving future therapeutic uses of CDK4/6 inhibition in a variety of cancers.

7. 对BCR-ABL1靶向治疗的反应和耐药性

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30146-X

慢性粒细胞白血病（CML）是由组成性活性BCR-ABL1融合酪氨酸激酶引起的，已成为分子靶向肿瘤治疗成功应用的范例。酪氨酸激酶抑制剂（TKI）伊马替尼的研制使慢性粒细胞白血病患者的预期寿命接近正常。降低药物结合亲和力的特异性点突变可以产生TKI耐药性，而第二代和第三代TKI在很大程度上缓解了这一问题。一些患者在没有已知的耐药突变的情况下产生TKI耐药，其潜在机制存在明显的异质性，但这种情况相对少见，大多数慢性期CML患者实现了长期的疾病控制。相反，TKI治疗在疾病晚期或BCR-ABL1阳性的急性淋巴细胞白血病中的反应是短暂的，其复发受BCR-ABL1激酶依赖和独立机制的驱动。此外，使用第二代TKIs的前线CML治疗产生更深的分子反应，使更多患者的疾病负担低于检测限。对于有深部分子反应的患者，多达一半的患者能够停止治疗。目前的工作集中在确定治疗策略，以推动更深的分子反应，使更多的病人尝试TKI中止。

Chronic myeloid leukemia (CML), caused by constitutively active BCR-ABL1 fusion tyrosine kinase, has served as a paradigm for successful application of molecularly targeted cancer therapy. The development of the tyrosine kinase inhibitor (TKI) imatinib allows patients with CML to experience near-normal life expectancy. Specific point mutations that decrease drug binding affinity can produce TKI resistance, and second- and third-generation TKIs largely mitigate this problem. Some patients develop TKI resistance without known resistance mutations, with significant heterogeneity in the underlying mechanism, but this is relatively uncommon, with the majority of patients with chronic phase CML achieving long-term disease control. In contrast, responses to TKI treatment are short lived in advanced phases of the disease or in BCR-ABL1-positive acute lymphoblastic leukemia, with relapse driven by both BCR-ABL1 kinase-dependent and -independent mechanisms. Additionally, the frontline CML treatment with second-generation TKIs produces deeper molecular responses, driving disease burden below the detection limit for a greater number of patients. For patients with deep molecular responses, up to half have been able to discontinue therapy. Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation.

8. 在KRAS驱动的肿瘤中靶向MAPK通路

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30153-7

KRAS突变发生在四分之一的人类癌症中，但还没有一种选择性药物被批准用于治疗这些肿瘤。尽管最近开发了阻断KRASG12C的药物，但大多数KRAS癌蛋白仍然是不可治疗的。在这里，我们通过比较KRAS驱动的肺和胰腺肿瘤的实验小鼠模型中获得的遗传信息和临床试验中选择性MAPK抑制剂的结果，回顾了近年来为验证有丝分裂原活化蛋白激酶（MAPK）通路的单个组分作为治疗KRAS突变癌的靶点所做的努力。我们还回顾了RAF1作为阻断KRAS突变癌的关键靶点的潜力。

KRAS mutations occur in a quarter of all of human cancers, yet no selective drug has been approved to treat these tumors. Despite the recent development of drugs that block KRASG12C, the majority of KRAS oncoproteins remain undruggable. Here, we review recent efforts to validate individual components of the mitogen-activated protein kinase (MAPK) pathway as targets to treat KRAS-mutant cancers by comparing genetic information derived from experimental mouse models of KRAS-driven lung and pancreatic tumors with the outcome of selective MAPK inhibitors in clinical trials. We also review the potential of RAF1 as a key target to block KRAS-mutant cancers.

9. 弥漫性大B细胞淋巴瘤遗传亚型的概率分类工具及其治疗意义

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30155-0

弥漫性大B细胞淋巴瘤（DLBCL）的精确药物治疗方法因其显著的遗传、表型和临床异质性而受到困扰。最近的多平台基因组学研究表明，DLBCL基因亚型的存在，使用聚类方法。在这里，我们描述了一种算法，根据患者的遗传特征，确定其淋巴瘤属于七种遗传亚型之一的概率。这种分类揭示了这些DLBCL亚型与各种惰性和结外淋巴瘤类型之间的遗传相似性，提示了共同的发病机制。这些基因亚型还具有不同的基因表达谱、免疫微环境和免疫化疗后的结果。基因亚型模型的功能分析突出了靶向治疗的明显弱点，支持在精密药物试验中使用这种分类。

The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.

10. 1000例儿童低级别胶质瘤的分子与临床综合分析

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30151-3

儿童低级别胶质瘤（pLGG）常由RAS有丝分裂原激活蛋白激酶（RAS/MAPK）途径的基因改变所驱动，但临床结果却显示出无法解释的变异性。为了解决这个问题，我们对一个超过1000个临床注释的pLGG的队列进行了研究。84%的病例有司机改变，而那些没有确定改变的病例也经常表现出RAS/MAPK通路的上调。pLGG可根据其蚀变类型进行广泛的分类。与SNV驱动的肿瘤相比，重排驱动的肿瘤诊断年龄较小，WHO组织学分级为I级，很少进展，很少导致死亡。临床分子的进一步亚分类将pLGG分层为危险类别。这些数据突出了pLGG亚型之间的生物学和临床差异，为未来的治疗改进开辟了道路。

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

11. CHD1的丢失通过染色质失调促进对AR靶向治疗耐药的异质性机制

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30101-X

转移性前列腺癌的特征是反复的基因组拷贝数改变，这些改变被认为有助于抵抗激素治疗。我们在活体小发夹RNA（shRNA）筛选730个前列腺癌基因时发现CHD1丢失是抗雄激素抵抗的原因。ATAC-seq和RNA-seq分析表明，CHD1缺失导致开放染色质和封闭染色质的整体变化以及相关的转录组变化。综合分析这些数据，结合基于CRISPR的功能筛选，确定了4种转录因子（NR3C1、POU3F2、NR2F1和TBX2）有助于抗雄激素抵抗，并激活非腔静脉谱系程序。因此，CHD1loss导致染色质失调，从而建立一种转录可塑性状态，通过异质性机制使抗雄激素抵抗出现。

Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

12. KMT2D缺乏会损害超级增强子，从而导致肺癌的糖酵解脆弱性

https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30106-9

表观遗传修饰剂在肺癌中常存在功能缺失突变，但其抑癌作用特征不明显。组蛋白甲基转移酶KMT2D（一种类似罗盘的酶，也称为MLL4）是肺癌中最高度失活的表观遗传修饰物之一。在这里，我们发现Kmt2d的肺特异性丢失促进小鼠的肺肿瘤发生，并上调促肿瘤发生的程序，包括糖酵解。糖酵解的药物抑制优先阻碍了携带KMT2D失活突变的人肺癌细胞的致瘤性。从机制上讲，Kmt2d丢失广泛损害了超级增强子/增强子的表观烯醇信号，包括用于昼夜节律抑制因子Per2的超级增强子。Kmt2d的丢失降低了调节多个糖酵解基因的PER2的表达。这些发现表明KMT2D是一种肺肿瘤抑制因子，KMT2D缺乏可导致糖酵解抑制剂的治疗脆弱性。

Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.